Marta E Alarcón-Riquelme1, Julie T Ziegler2, Julio Molineros1, Timothy D Howard2, Andrés Moreno-Estrada3, Elena Sánchez-Rodríguez4, Hannah C Ainsworth2, Patricia Ortiz-Tello3, Mary E Comeau2, Astrid Rasmussen1, Jennifer A Kelly1, Adam Adler1, Eduardo M Acevedo-Vázquez5, Jorge Mariano Cucho-Venegas5, Ignacio García-De la Torre6, Mario H Cardiel7, Pedro Miranda8, Luis J Catoggio9, Marco Maradiaga-Ceceña10, Patrick M Gaffney1, Timothy J Vyse11, Lindsey A Criswell12, Betty P Tsao13, Kathy L Sivils1, Sang-Cheol Bae14, Judith A James15, Robert P Kimberly16, Kenneth M Kaufman17, John B Harley17, Jorge A Esquivel-Valerio18, José F Moctezuma19, Mercedes A García20, Guillermo A Berbotto21, Alejandra M Babini22, Hugo Scherbarth23, Sergio Toloza24, Vicente Baca25, Swapan K Nath1, Carlos Aguilar Salinas26, Lorena Orozco27, Teresa Tusié-Luna28, Raphael Zidovetzki29, Bernardo A Pons-Estel30, Carl D Langefeld2, Chaim O Jacob31. 1. Oklahoma Medical Research Foundation, Oklahoma City. 2. Wake Forest School of Medicine, Winston-Salem, North Carolina. 3. Stanford University School of Medicine, Stanford, California, and Laboratorio Nacional de Genómica para la Biodiversidad, Centro de Investigación y de Estudios Avanzados del Instituto Politécnico Nacional, Irapuato, Mexico. 4. Icahn School of Medicine at Mount Sinai, New York, New York. 5. Hospital Nacional Guillermo Almenara Irigoyen, Lima, Peru. 6. Hospital General de Occidente, Zapopan, Mexico. 7. Centro de Investigación Clínica de Morelia, Morelia, Mexico. 8. Centro de Estudios Reumatológicos, Santiago, Chile. 9. Hospital Italiano de Buenos Aires, Buenos Aires, Argentina. 10. Hospital General de Culiacán, Culiacán, Mexico. 11. King's College London, London, UK. 12. University of California, San Francisco. 13. University of California, Los Angeles. 14. Hanyang University Hospital for Rheumatic Diseases, Seoul, Republic of Korea. 15. Oklahoma Medical Research Foundation and University of Oklahoma Health Sciences Center, Oklahoma City. 16. University of Alabama at Birmingham. 17. Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio. 18. Hospital Universitario Dr. José Eleuterio González Universidad Autonoma de Nuevo León, Monterrey, Mexico. 19. Hospital General de México, Mexico City, Mexico. 20. Hospital Interzonal General de Agudos General San Martin, La Plata, Argentina. 21. Hospital Escuela Eva Perón, Granadero Baigorria, Argentina. 22. Hospital Italiano de Córdoba, Córdoba, Argentina. 23. Hospital Interzonal General de Agudos Oscar E. Alende, Mar del Plata, Argentina. 24. Hospital Interzonal San Juan Bautista, San Fernando del Valle de Catamarca, Argentina. 25. Hospital de Peditaria, Centro Médico Nacional Siglo XXI, Instituto Mexicano del Seguro Social, Mexico City, Mexico. 26. Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán, Mexico City, Mexico. 27. Instituto Nacional de Medicina Genómica, Mexico City, Mexico. 28. Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán and Instituto de Investigaciones Biomédicas de la Universidad Nacional Autónoma de México, Mexico City, Mexico. 29. University of California, Riverside. 30. Sanatorio Parque, Rosario, Argentina. 31. University of Southern California School of Medicine, Los Angeles.
Abstract
OBJECTIVE: Systemic lupus erythematosus (SLE) is a chronic autoimmune disease with a strong genetic component. We undertook the present work to perform the first genome-wide association study on individuals from the Americas who are enriched for Native American heritage. METHODS: We analyzed 3,710 individuals from the US and 4 countries of Latin America who were diagnosed as having SLE, and healthy controls. Samples were genotyped with HumanOmni1 BeadChip. Data on out-of-study controls genotyped with HumanOmni2.5 were also included. Statistical analyses were performed using SNPtest and SNPGWA. Data were adjusted for genomic control and false discovery rate. Imputation was performed using Impute2 and, for classic HLA alleles, HiBag. Odds ratios (ORs) and 95% confidence intervals (95% CIs) were calculated. RESULTS: The IRF5-TNPO3 region showed the strongest association and largest OR for SLE (rs10488631: genomic control-adjusted P [Pgcadj ] = 2.61 × 10(-29), OR 2.12 [95% CI 1.88-2.39]), followed by HLA class II on the DQA2-DQB1 loci (rs9275572: Pgcadj = 1.11 × 10(-16), OR 1.62 [95% CI 1.46-1.80] and rs9271366: Pgcadj = 6.46 × 10(-12), OR 2.06 [95% CI 1.71-2.50]). Other known SLE loci found to be associated in this population were ITGAM, STAT4, TNIP1, NCF2, and IRAK1. We identified a novel locus on 10q24.33 (rs4917385: Pgcadj = 1.39 × 10(-8)) with an expression quantitative trait locus (eQTL) effect (Peqtl = 8.0 × 10(-37) at USMG5/miR1307), and several new suggestive loci. SLE risk loci previously identified in Europeans and Asians were corroborated. Local ancestry estimation showed that the HLA allele risk contribution is of European ancestral origin. Imputation of HLA alleles suggested that autochthonous Native American haplotypes provide protection against development of SLE. CONCLUSION: Our results demonstrate that studying admixed populations provides new insights in the delineation of the genetic architecture that underlies autoimmune and complex diseases.
OBJECTIVE:Systemic lupus erythematosus (SLE) is a chronic autoimmune disease with a strong genetic component. We undertook the present work to perform the first genome-wide association study on individuals from the Americas who are enriched for Native American heritage. METHODS: We analyzed 3,710 individuals from the US and 4 countries of Latin America who were diagnosed as having SLE, and healthy controls. Samples were genotyped with HumanOmni1 BeadChip. Data on out-of-study controls genotyped with HumanOmni2.5 were also included. Statistical analyses were performed using SNPtest and SNPGWA. Data were adjusted for genomic control and false discovery rate. Imputation was performed using Impute2 and, for classic HLA alleles, HiBag. Odds ratios (ORs) and 95% confidence intervals (95% CIs) were calculated. RESULTS: The IRF5-TNPO3 region showed the strongest association and largest OR for SLE (rs10488631: genomic control-adjusted P [Pgcadj ] = 2.61 × 10(-29), OR 2.12 [95% CI 1.88-2.39]), followed by HLA class II on the DQA2-DQB1 loci (rs9275572: Pgcadj = 1.11 × 10(-16), OR 1.62 [95% CI 1.46-1.80] and rs9271366: Pgcadj = 6.46 × 10(-12), OR 2.06 [95% CI 1.71-2.50]). Other known SLE loci found to be associated in this population were ITGAM, STAT4, TNIP1, NCF2, and IRAK1. We identified a novel locus on 10q24.33 (rs4917385: Pgcadj = 1.39 × 10(-8)) with an expression quantitative trait locus (eQTL) effect (Peqtl = 8.0 × 10(-37) at USMG5/miR1307), and several new suggestive loci. SLE risk loci previously identified in Europeans and Asians were corroborated. Local ancestry estimation showed that the HLA allele risk contribution is of European ancestral origin. Imputation of HLA alleles suggested that autochthonous Native American haplotypes provide protection against development of SLE. CONCLUSION: Our results demonstrate that studying admixed populations provides new insights in the delineation of the genetic architecture that underlies autoimmune and complex diseases.
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